• Gene editing Nobel Prize in Chemistry for scientists Charpentier and Doudna for the development of "CRISPR scissors"

  • Interview Jennifer Doudna: "I am not convinced of the need to edit human embryos to treat diseases"

Traveling back in time

has allowed an

international research group to reconstruct ancient bacterial proteins that may have existed hundreds of millions of years ago.

With these resurrected proteins, they have assembled a new CRISPR-Cas system

, the famous genetic editing tool that is used, among multiple applications, to develop treatments against various diseases, such as ALS or cancer.

The CRISPR-Cas system is actually a

defense mechanism of bacteria

against viruses: instead of developing antibodies against pathogens, prokaryotic organisms (bacteria and archaea) are

left

with small fragments of the genetic material of viruses that have infected others. their ancestors.

This ability to recognize DNA sequences, as if they were molecular scissors, is the basis for the development of CRISPR-Cas technology that allows cutting and pasting pieces of genetic material in any cell.

To perfect it, laboratories around the world have launched themselves in search of bacteria in the most remote places (Yellowstone Park, Antarctica, the Mariana Trench, or the top of Everest).

They look for microorganisms that do not normally coexist with humans.

The current CRISPR-Cas9 technology is based on

Streptococcus pyogenes

, a bacterium against which the majority of the population has developed antibodies, and this makes its use in a therapeutic context difficult.

A treasure from the past

The originality of the research that appears today in the scientific journal

Nature Microbiology

lies in the fact that instead of traveling through space, researchers have gone back in time.

This is how ancestors of the CRISPR gene-editing tool have been resurrected as far back as 2.6 billion years, which could lead to a

new and improved version

of this technology.

The finding is the result of a collaboration of more than four years between various centers and laboratories, initiated by

Raúl Pérez-Jiménez

(Ikerbasque researcher at CIC nanoGUNE);

Francis Mojica

(University of Alicante and discoverer of the CRISPR-Cas technique), and

Lluís Montoliu

(National Center for Biotechnology of the CSIC and the Cyber ​​for Rare Diseases), and in which

Marc Güell

(Pompeu Fabra University) also participates;

Miguel Ángel Moreno-Pelayo

(Ramón y Cajal-Irycis Hospital), and

Benjamin Kleinstiver

(Massachusetts General Hospital);

a whole group of

heavyweights

from the gene editing and CRISPR-Cas research community.

A capacity maintained over the years

For this study, they have carried out the

computer reconstruction of the ancestral Cas proteins (anCas)

, synthesized them and confirmed their functionality, a fact that stands out to this medium Lluís Montoliu, head of the team that has functionally validated the ancestral Cass in human cells in culture: "It is amazing that we can resurrect Cas proteins that must have existed billions of years ago and find that they

maintain their editing ability

. Although the ability to edit seems to decrease as we move further back in time, it still exists."

He also comments that the oldest ancestral Cass see their specificity vanish, which could result in greater versatility;

also, that instead of cutting the two DNA strands, as current nucleases do, they prefer to

cut single-stranded molecules

, a fact "compatible with the evolution that we believe took place at the origin of life, when there was a world of RNA, single-stranded nucleic acids.

What we would have predicted we would like to have found is exactly what we have found

."

For Raúl Pérez-Jiménez, whose work in the field of

paleoenzymology

allows him to study the

evolution of proteins from the origin of life to the present day

, "current systems are very complex and are adapted to function within a bacterium. When the system is used outside that environment, for example, in human cells, the immune system causes a rejection and there are also certain molecular restrictions that limit its use.Interestingly, in ancestral systems some of these restrictions disappear, which gives them a greater versatility for new applications".

In the field of application of the work, the professor at the University of Alicante and discoverer of the CRISPR-Cas technique, Francis Mojica, values ​​that "it represents an original way of approaching the development of CRISPR tools to

generate new instruments

and improve the derivatives of those existing in current organisms".

In the study they have verified that the "CRISPR-anCas" system works as a genetic editor in human cells;

They have also found that antibodies against Cas9 (current system) do not recognize ancient nucleases, a key condition for their application in gene therapy.

"The next step is

to verify the efficacy and safety in animal models

of diseases, before considering its use in therapy," announces Montoliu about a potential tool that can open up new paths in gene editing.

According to the criteria of The Trust Project

Know more

  • bioscience

  • Genetics